Heart failure is one of the leading causes of death and disability worldwide. Left ventricle remodeling, fibrosis, and ischemia/reperfusion injury all contribute to the deterioration of cardiac ...function and predispose to the onset of heart failure. Adenosine monophosphate-activated protein kinase (AMPK) is the universally recognized energy sensor which responds to low ATP levels and restores cellular metabolism. AMPK activation controls numerous cellular processes and, in the heart, it plays a pivotal role in preventing onset and progression of disease. Excessive reactive oxygen species (ROS) generation, known as oxidative stress, can activate AMPK, conferring an additional role of AMPK as a redox-sensor. In this review, we discuss recent insights into the crosstalk between ROS and AMPK. We describe the molecular mechanisms by which ROS activate AMPK and how AMPK signaling can further prevent heart failure progression. Ultimately, we review the potential therapeutic approaches to target AMPK for the treatment of cardiovascular disease and prevention of heart failure.
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•Excessive reactive oxygen species generation can activate AMPK, conferring an additional role to AMPK as a redox sensor.•AMPK activation reduces oxidative stress by acting on Nox, mitochondria and antioxidant enzyme expression.•AMPK plays a crucial role in controlling oxidative stress in ischemia-reperfusion, cardiac hypertrophy or atherosclerosis.•By limiting ROS, AMPK protects the heart from failure and can prevent both HFpEF and HFrEF.
Abstract Fibrosis is a general term encompassing a plethora of pathologies that span all systems and is marked by increased deposition of collagen. Injury of variable etiology gives rise to complex ...cascades involving several cell-types and molecular signals, leading to the excessive accumulation of extracellular matrix that promotes fibrosis and eventually leads to organ failure. Cardiac fibrosis is a dynamic process associated notably with ischemia, hypertrophy, volume- and pressure-overload, aging and diabetes mellitus. It has profoundly deleterious consequences on the normal architecture and functioning of the myocardium and is associated with considerable mortality and morbidity. The AMP-activated protein kinase (AMPK) is a ubiquitously expressed cellular energy sensor and an essential component of the adaptive response to cardiomyocyte stress that occurs during ischemia. Nevertheless, its actions extend well beyond its energy-regulating role and it appears to possess an essential role in regulating fibrosis of the myocardium. In this review paper, we will summarize the main elements and crucial players of cardiac fibrosis. In addition, we will provide an overview of the diverse roles of AMPK in the heart and discuss in detail its implication in cardiac fibrosis. Lastly, we will highlight the recently published literature concerning AMPK-targeting current therapy and novel strategies aiming to attenuate fibrosis.
Glucose transporters are essential for the heart to sustain its function. Due to its nature as a high energy-consuming organ, the heart needs to catabolize a huge quantity of metabolic substrates. ...For optimized energy production, the healthy heart constantly switches between various metabolites in accordance with substrate availability and hormonal status. This metabolic flexibility is essential for the maintenance of cardiac function. Glucose is part of the main substrates catabolized by the heart and its use is fine-tuned via complex molecular mechanisms that include the regulation of the glucose transporters GLUTs, mainly GLUT4 and GLUT1. Besides GLUTs, glucose can also be transported by cotransporters of the sodium-glucose cotransporter (SGLT) (SLC5 gene) family, in which SGLT1 and SMIT1 were shown to be expressed in the heart. This SGLT-mediated uptake does not seem to be directly linked to energy production but is rather associated with intracellular signalling triggering important processes such as the production of reactive oxygen species. Glucose transport is markedly affected in cardiac diseases such as cardiac hypertrophy, diabetic cardiomyopathy and heart failure. These alterations are not only fingerprints of these diseases but are involved in their onset and progression. The present review will depict the importance of glucose transport in healthy and diseased heart, as well as proposed therapies targeting glucose transporters.
AMP-activated protein kinase (AMPK) has been shown to inhibit cardiac hypertrophy. Here, we show that submaximal AMPK activation blocks cardiomyocyte hypertrophy without affecting downstream targets ...previously suggested to be involved, such as p70 ribosomal S6 protein kinase, calcineurin/nuclear factor of activated T cells (NFAT) and extracellular signal-regulated kinases. Instead, cardiomyocyte hypertrophy is accompanied by increased protein O-GlcNAcylation, which is reversed by AMPK activation. Decreasing O-GlcNAcylation by inhibitors of the glutamine:fructose-6-phosphate aminotransferase (GFAT), blocks cardiomyocyte hypertrophy, mimicking AMPK activation. Conversely, O-GlcNAcylation-inducing agents counteract the anti-hypertrophic effect of AMPK. In vivo, AMPK activation prevents myocardial hypertrophy and the concomitant rise of O-GlcNAcylation in wild-type but not in AMPKα2-deficient mice. Treatment of wild-type mice with O-GlcNAcylation-inducing agents reverses AMPK action. Finally, we demonstrate that AMPK inhibits O-GlcNAcylation by mainly controlling GFAT phosphorylation, thereby reducing O-GlcNAcylation of proteins such as troponin T. We conclude that AMPK activation prevents cardiac hypertrophy predominantly by inhibiting O-GlcNAcylation.
This chapter summarizes AMPK function in the regulation of substrate and energy metabolism with the main emphasis on carbohydrate and lipid metabolism, protein turnover, mitochondrial biogenesis, and ...whole-body energy homeostasis. AMPK acts as whole-body energy sensor and integrates different signaling pathway to meet both cellular and body energy requirements while inhibiting energy-consuming processes but also activating energy-producing ones. AMPK mainly promotes glucose and fatty acid catabolism, whereas it prevents protein, glycogen, and fatty acid synthesis.
Biological tissues comprise a spatially complex structure, composition and organization at the microscale, named the microstructure. Given the close structure-function relationships in tissues, ...structural characterization is essential to fully understand the functioning of healthy and pathological tissues, as well as the impact of possible treatments. Here, we present a nondestructive imaging approach to perform quantitative 3D histo(patho)logy of biological tissues, termed Cryogenic Contrast-Enhanced MicroCT (cryo-CECT). By combining sample staining, using an X-ray contrast-enhancing staining agent, with freezing the sample at the optimal freezing rate, cryo-CECT enables 3D visualization and structural analysis of individual tissue constituents, such as muscle and collagen fibers. We applied cryo-CECT on murine hearts subjected to pressure overload following transverse aortic constriction surgery. Cryo-CECT allowed to analyze, in an unprecedented manner, the orientation and diameter of the individual muscle fibers in the entire heart, as well as the 3D localization of fibrotic regions within the myocardial layers. We foresee further applications of cryo-CECT in the optimization of tissue/food preservation and donor banking, showing that cryo-CECT also has clinical and industrial potential.
It is now becoming evident that the liver has an important role in the control of whole body metabolism of energy nutrients.
In this review, we focus on recent findings showing that AMP-activated ...protein kinase (AMPK) plays a major role in the control
of hepatic metabolism. AMPK integrates nutritional and hormonal signals to promote energy balance by switching on catabolic
pathways and switching off ATP-consuming pathways, both by short-term effects on phosphorylation of regulatory proteins and
by long-term effects on gene expression. Activation of AMPK in the liver leads to the stimulation of fatty acid oxidation
and inhibition of lipogenesis, glucose production and protein synthesis. Medical interest in the AMPK system has recently
increased with the demonstration that AMPK could mediate some of the effects of the fat cell-derived adiponectin and the antidiabetic
drugs metformin and thiazolidinediones. These findings reinforce the idea that pharmacological activation of AMPK may provide,
through signalling and metabolic and gene expression effects, a new strategy for the management of metabolic hepatic disorders
linked to type 2 diabetes and obesity.
Sex Differences of the Diabetic Heart Fourny, Natacha; Beauloye, Christophe; Bernard, Monique ...
Frontiers in physiology,
05/2021, Letnik:
12
Journal Article
Recenzirano
Odprti dostop
Type 2 diabetes is a chronic disease associated with micro- and macro-vascular complications, including myocardial ischemia, and also with a specific and intrinsic cardiac dysfunction called diabetic ...cardiomyopathy (DCM). Both clinical and animal studies demonstrate significant sex differences in prevalence, pathophysiology, and outcomes of cardiovascular diseases (CVDs), including those associated with diabetes. The increased risk of CVDs with diabetes is higher in women compared to men with 50% higher risk of coronary artery diseases and increased mortality when exposed to acute myocardial infarction. Clinical studies also reveal a sexual dimorphism in the incidence and outcomes of DCM. Based on these clinical findings, growing experimental research was initiated to understand the impact of sex on CVDs associated with diabetes and to identify the molecular mechanisms involved. Endothelial dysfunction, atherosclerosis, coagulation, and fibrosis are mechanisms found to be sex-differentially modulated in the diabetic cardiovascular system. Recently, impairment of energy metabolism also emerged as a determinant of multiple CVDs associated with diabetes. Therefore, future studies should thoroughly analyze the sex-specific metabolic determinants to propose new therapeutic targets. With current medicine tending toward more personalized care of patients, we finally propose to discuss the importance of sex as determinant in the treatment of diabetes-associated cardiac diseases to promote a more systemic inclusion of both males and females in clinical and preclinical studies.
Abstract
Sepsis capillary leak syndrome (SCLS) is an independent prognostic factor for poor sepsis outcome. We previously demonstrated that α1AMP-activated protein kinase (α1AMPK) prevents ...sepsis-induced vascular hyperpermeability by mechanisms involving VE-cadherin (VE-Cad) stabilization and activation of p38 mitogen activated protein kinase/heat shock protein of 27 kDa (p38MAPK/HSP27) pathway. Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, has recently been proven to activate AMPK in endothelial cells. Therefore, we hypothesized that canagliflozin could be of therapeutic potential in patients suffering from SCLS. We herein report that canagliflozin, used at clinically relevant concentrations, counteracts lipopolysaccharide-induced vascular hyperpermeability and albumin leakage in wild-type, but not in endothelial-specific α1AMPK-knockout mice. In vitro, canagliflozin was demonstrated to activate α1AMPK/p38MAPK/HSP27 pathway and to preserve VE-Cad’s integrity in human endothelial cells exposed to human septic plasma. In conclusion, our data demonstrate that canagliflozin protects against SCLS via an α1AMPK-dependent pathway, and lead us to consider novel therapeutic perspectives for this drug in SCLS.
Although sodium glucose cotransporter 1 (SGLT1) has been identified as one of the major SGLT isoforms expressed in the heart, its exact role remains elusive. Evidence using phlorizin, the most common ...inhibitor of SGLTs, has suggested its role in glucose transport. However, phlorizin could also affect classical facilitated diffusion via glucose transporters (GLUTs), bringing into question the relevance of SGLT1 in overall cardiac glucose uptake. Accordingly, we assessed the contribution of SGLT1 in cardiac glucose uptake using the SGLT1 knockout mouse model, which lacks exon 1. Glucose uptake was similar in cardiomyocytes isolated from SGLT1-knockout (
KO) and control littermate (WT) mice either under basal state, insulin, or hyperglycemia. Similarly, in vivo basal and insulin-stimulated cardiac glucose transport measured by micro-PET scan technology did not differ between WT and
KO mice. Micromolar concentrations of phlorizin had no impact on glucose uptake in either isolated WT or
KO-derived cardiomyocytes. However, higher concentrations (1 mM) completely inhibited insulin-stimulated glucose transport without affecting insulin signaling nor GLUT4 translocation independently from cardiomyocyte genotype. Interestingly, we discovered that mouse and human hearts expressed a shorter
transcript, leading to SGLT1 protein lacking transmembrane domains and residues involved in glucose and sodium bindings. In conclusion, cardiac SGLT1 does not contribute to overall glucose uptake, probably due to the expression of
transcript variant. The inhibitory effect of phlorizin on cardiac glucose uptake is SGLT1-independent and can be explained by GLUT transporter inhibition. These data open new perspectives in understanding the role of SGLT1 in the heart.
Ever since the discovery of its expression in the heart, SGLT1 has been considered as similar as the intestine and a potential contributor to cardiac glucose transport. For the first time, we have demonstrated that a
transcript variant is present in the heart that has no significant impact on cardiac glucose handling.
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